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1.
ACS Med Chem Lett ; 9(12): 1164-1169, 2018 Dec 13.
Artigo em Inglês | MEDLINE | ID: mdl-30613320

RESUMO

IκB kinase ß (IKKß or IKK2) is a key regulator of nuclear factor kappa B (NF-κB) and has received attention as a therapeutic target. Herein we report on the optimization of a series of 3,5-disubstituted-indole-7-carboxamides for oral activity. In doing so, we focused attention on potency, ligand efficiency (LE), and physicochemical properties and have identified compounds 24 and (R)-28 as having robust in vivo activity.

2.
J Med Chem ; 52(8): 2280-8, 2009 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-19317397

RESUMO

A series of saligenin alkoxyalkylphenylsulfonamide beta(2) adrenoceptor agonists were prepared by reacting a protected saligenin oxazolidinone with alkynyloxyalkyl bromides, followed by Sonogashira reaction, hydrogenation, and deprotection. The meta-substituted primary sulfonamide was more potent than the para- and the ortho-analogues. Primary sulfonamides were more potent than the secondary and tertiary analogues. The onset and duration of action in vitro of selected compounds was assessed on isolated superfused guinea pig trachea. Sulfonamide 29b had the best profile of potency, selectivity, onset, and duration of action on both guinea pig trachea and human bronchus. Furthermore, 29b was found to have low oral bioavailability in rat and dog and also to have long duration of action in an in vivo model of bronchodilation. Crystalline salts of 29b were identified that had suitable properties for inhaled administration. A proposed binding mode for 29b to the beta(2)-receptor is presented.


Assuntos
2-Hidroxifenetilamina/análogos & derivados , Agonistas de Receptores Adrenérgicos beta 2 , Sulfonamidas/síntese química , 2-Hidroxifenetilamina/síntese química , 2-Hidroxifenetilamina/química , 2-Hidroxifenetilamina/farmacologia , Administração Oral , Albuterol/análogos & derivados , Albuterol/química , Albuterol/farmacologia , Animais , Disponibilidade Biológica , Brônquios/efeitos dos fármacos , Brônquios/fisiologia , Células CHO , Cricetinae , Cricetulus , AMP Cíclico/biossíntese , Cães , Cobaias , Humanos , Técnicas In Vitro , Microssomos/metabolismo , Modelos Moleculares , Contração Muscular/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , Músculo Liso/fisiologia , Ratos , Xinafoato de Salmeterol , Estereoisomerismo , Relação Estrutura-Atividade , Sulfonamidas/química , Sulfonamidas/farmacologia , Traqueia/efeitos dos fármacos , Traqueia/fisiologia
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